The present invention concerns 2-oxo-1-pyrrolidine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
European Patent No. 0 162 036 B1 discloses the compound (S)-xcex1-ethyl-2-oxo-1-pyrrolidine acetamide, which is known under the International Nonproprietary Name of levetiracetam.
Levetiracetam, a laevorotary compound, is disclosed as a protective agent for the treatment and prevention of hypoxic and ischemic type aggressions of the central nervous system. This compound is also effective in the treatment of epilepsy, a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer (R)-xcex1-ethyl-2-oxo-1-pyrrolidine acetamide, also known from European Patent No. 0 165 919 B1, completely lacks activity (A. J. GOWER et al., Eur. J. Pharmacol., 222, (1992), 193-203).
Racemic xcex1-ethyl-2-oxo-1-pyrrolidine acetamide and analogs thereof are known from British Patent No. 1 309 692. U.S. Pat. No. 3,459,738 discloses derivatives of 2-oxo-1-pyrrolidine acetamide. European Patent No. 0 645 139 B 1 discloses the anxiolytic activity of levetiracetam. PCT Application No. PCT/EP00/11808 discloses the use of levetiracetam for the curative and/or prophylactic treatment of bipolar disorders, migraine, chronic or neuropathic pain as well as combinations of levetiracetam with at least one compound inducing neural inhibition mediated by GABAA receptors.
It has now surprisingly been found that certain analogs of levetiracetam, particulary those bearing further substitution in the pyrrolidone ring, demonstrate markedly improved therapeutic properties.
In one aspect, the invention therefore provides a compound having the formula I or a pharmaceutically acceptable salt thereof, 
wherein
X is xe2x80x94CA1NR5R6 or xe2x80x94CA1OR7 or xe2x80x94CA1xe2x80x94R8 or CN;
A1 and A2 are independently oxygen, sulfur or xe2x80x94NR9;
R1 is hydrogen, alkyl, aryl or xe2x80x94CH2xe2x80x94R1a wherein R1a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;
R2, R3 and R4 are the same or different and each is independently hydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, or an oxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfinyl derivative;
R2a, R3a and R4a are the same or different and each is independently hydrogen, halogen, alkyl, alkenyl, alkynyl or aryl;
R5, R6, R7and R9 are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative; and
R8 is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or a thio derivative;
with the provisos that at least one of as R2, R3, R4, R2a, R3a and R4a is other than hydrogen; and that when the compound is a mixture of all possible isomers, X is xe2x80x94CONR5R6, A2 is oxygen and R1 is hydrogen, methyl, ethyl or propyl then substitution on the pyrollidine ring is other than mono-, di-, or tri-methyl or mono-ethyl; and that when R1, R2, R4, R2a, R3a and R4a are each hydrogen, A2 is oxygen and X is CONR5R6 then R3 is different from carboxy, ester, amido, substituted oxo-pyrrolidine, hydroxy, oxy derivative, amino, amino derivatives, methyl, naphthyl, phenyl optionally substituted by oxy derivatives or in the para position by an halogen atom.
In the definitions set forth below, unless otherwise stated, R11 and R12 are the same or different and each is independently amido, alkyl, alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or an oxy derivative, thio derivative, acyl derivative, amino derivative, sulfonyl derivative, or sulfinyl derivative, each optionally substituted with any suitable group, including, but not limited to, one or more moieties selected from lower alkyl or other groups as described below as substituents for alkyl.
The term xe2x80x9coxy derivativexe2x80x9d, as used herein is defined as including xe2x80x94Oxe2x80x94R11 groups wherein R11 is as defined above except for xe2x80x9coxy derivativexe2x80x9d. Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate.
The term xe2x80x9cthio derivativexe2x80x9d as used herein, is defined as including xe2x80x94Sxe2x80x94R11 groups wherein R11 is as defined above except for xe2x80x9cthio derivativexe2x80x9d. Non-limiting examples are alkylthio, alkenylthio, alkynylthio and arylthio
The term xe2x80x9camino derivativexe2x80x9d as used herein, is defined as including xe2x80x94NHR11 or xe2x80x94NR11R12 groups wherein R11 and R12 are as defined above. Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl- and arylamino or mixed amino.
The term xe2x80x9cacyl derivativexe2x80x9d as used herein, represents a radical derived from carboxylic acid and thus is defined as including groups of the formula R11xe2x80x94CO, wherein R11 is as defined above and may also be hydrogen. Non-limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.
The term xe2x80x9csulfonyl derivativexe2x80x9d as used herein, is defined as including a group of the formula xe2x80x94SO2xe2x80x94R11, wherein R11 is as defined above except for xe2x80x9csulfonyl derivativexe2x80x9d. Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.
The term xe2x80x9csulfinyl derivativexe2x80x9d as used herein, is defined as including a group of the formula xe2x80x94SOxe2x80x94R11, wherein R11 is as defined above except for xe2x80x9csulfinyl derivativexe2x80x9d. Non-limiting examples are alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.
The term xe2x80x9calkylxe2x80x9d, as used herein, is defined as including saturated, monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and containing 1-20 carbon atoms, preferably 1-6 carbon atoms for non-cyclic alkyl and 3-6 carbon atoms for cycloalkyl (in these two preferred cases, unless otherwise specified, xe2x80x9clower alkylxe2x80x9d) Alkyl moieties may optionally be substituted by 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, oxyester, oxyamido, heterocycle, vinyl, C1-5-alkoxy, C6-10-aryloxy and C6-10-aryl.
Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, and 2,2,2-trimethylethyl each optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro and cyano, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.
The term xe2x80x9calkenylxe2x80x9d as used herein, is defined as including both branched and unbranched, unsaturated hydrocarbon radicals having at least one double bond such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (=allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, and the like and being optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl and heterocycle such as mono- and di-halo vinyl where halo is fluoro, chloro or bromo.
The term xe2x80x9calkynylxe2x80x9d as used herein, is defined as including a monovalent branched or unbranched hydrocarbon radical containing at least one carbon-carbon triple bond, for example ethynyl, 2-propynyl (=propargyl), and the like and being optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl and heterocycle, such as haloethynyl.
When present as bridging groups, alkyl, alkenyl and alkynyl represent straight- or branched chains, C1-12, preferably C1-4-alkylene or C2-12-, preferably C2-4-alkenylene or -alkynylene moieties respectively.
Groups where branched derivatives are conventionally qualified by prefixes such as xe2x80x9cnxe2x80x9d, xe2x80x9csecxe2x80x9d, xe2x80x9cisoxe2x80x9d and the like (e.g. xe2x80x9cn-propylxe2x80x9d, xe2x80x9csec-butylxe2x80x9d) are in the n-form unless otherwise stated.
The term xe2x80x9carylxe2x80x9d as used herein, is defined as including an organic radical derived from an aromatic hydrocarbon consisting of 1-3 rings and containing 6-30 carbon atoms by removal of one hydrogen, such as phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl, alkylthio, oxyester, oxyamido, aryl, C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl, C1-6-haloalkyl. Aryl radicals are preferably monocyclic containing 6-10 carbon atoms. Preferred aryl groups are phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently selected from halogen, nitro, amino, azido, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl, C1-6-haloalkyl and phenyl.
The term xe2x80x9chalogenxe2x80x9d, as used herein, includes an atom of Cl, Br, F, I.
The term xe2x80x9chydroxyxe2x80x9d, as used herein, represents a group of the formula xe2x80x94OH.
The term xe2x80x9cthiolxe2x80x9d, as used herein, represents a group of the formula xe2x80x94SH.
The term xe2x80x9ccyanoxe2x80x9d, as used herein, represents a group of the formula xe2x80x94CN.
The term xe2x80x9cnitroxe2x80x9d, as used herein, represents a group of the formula xe2x80x94NO2.
The term xe2x80x9cnitrooxyxe2x80x9d, as used herein, represents a group of the formula xe2x80x94ONO2.
The term xe2x80x9caminoxe2x80x9d, as used herein, represents a group of the formula xe2x80x94NH2.
The term xe2x80x9cazidoxe2x80x9d, as used herein, represents a group of the formula xe2x80x94N3 
The term xe2x80x9ccarboxyxe2x80x9d, as used herein, represents a group of the formula xe2x80x94COOH.
The term xe2x80x9csulfonic acidxe2x80x9d, as used herein, represents a group of the formula xe2x80x94SO3H.
The term xe2x80x9csulfonamidexe2x80x9d, as used herein, represents a group of the formula xe2x80x94SO2NH2.
The term xe2x80x9cesterxe2x80x9d as used herein is defined as including a group of formula xe2x80x94COOxe2x80x94R11 wherein R11 is as defined above except oxy derivative, thio derivative or amino derivative.
The term xe2x80x9cetherxe2x80x9d is defined as including a group selected from C1-50-straight or branched alkyl, or C2-50-straight or branched alkenyl or alkynyl groups or a combination of the same, interrupted by one or more oxygen atoms.
The term xe2x80x9camidoxe2x80x9d is defined as including a group of formula xe2x80x94CONH2 or xe2x80x94CONHR11 or xe2x80x94CONR11R12 wherein R11 and R12 are as defined above.
The term xe2x80x9cheterocyclexe2x80x9d, as used herein is defined as including an aromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure and optionally, one of the carbon of the carbocyclic ring structure may be replaced by a carbonyl. Non-limiting examples of aromatic heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, thianthrenyl, benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenothiazinyl, furazanyl, isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl optionally substituted by alkyl or as described above for the alkyl groups. Non-limiting examples of non aromatic heterocycles are tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl, sugar moieties (i.e. glucose, pentose, hexose, ribose, fructose, which may also be substituted) or the same which can optionally be substituted with any suitable group, including but not limited to one or more moieties selected from lower alkyl, or other groups as described above for the alkyl groups. The term xe2x80x9cheterocyclexe2x80x9d also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring or where a monocyclic heterocyclic group is bridged by an alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl, 8-azabicyclo(3.2.1)octanyl.
In the above definitions it is to be understood that when a substituent such as R2, R3, R4, R2a, R3a, R4a, R5, R6, R7, R8 is attached to the rest of the molecule via a heteroatom or a carbonyl, a straight- or branched chain, C1-12-, preferably C1-4-alkylene or C2-12, preferably C2-4-alkenylene or -alkynylene bridge may optionally be interposed between the heteroatom or the carbonyl and the point of attachment to the rest of the molecule.
Preferred examples of X are xe2x80x94COO R7 or xe2x80x94CONR5R6, wherein R5, R6 and R7 are preferably hydrogen, C1-4-alkyl, phenyl or alkylphenyl.
Preferably X is carboxy or xe2x80x94CONR5R6, wherein R5 and R6 are preferably hydrogen, C1-4-alkyl, phenyl or alkylphenyl, especially xe2x80x94CONH2.
Preferably A1 and A2 are each oxygen.
Preferably R1 is hydrogen, alkyl, especially C1-12 alkyl, particularly lower alkyl or aryl especially phenyl.
Examples of preferred R1 groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or ter-butyl, 2,2,2-trimethylethyl each optionally attached via a methylene bridge or the same substituted by at least one halogen atom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.
R1 as ethyl is especially preferred.
Preferably R2 and R2a are independently hydrogen, halogen or alkyl, especially lower alkyl.
Examples of preferred R and R2a groups are independently hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least one halogen atom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.
Especially at least one and most preferably both of R2 and R2a are hydrogen.
Preferably R3a, R4 and R4a are independently hydrogen, alkyl, especially methyl or ethyl or aryl especially phenyl or aralkyl, especially benzyl.
Examples of preferred R3a, R4 and R4a groups are independently hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least one halogen atom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.
Especially at least one and most preferably both of R4 and R4a are hydrogen.
R3a is particularly hydrogen or alkyl, especially lower alkyl and is most preferably hydrogen.
Preferably R3 is hydrogen, C1-12-alkyl, especially C1-6-alkyl, each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ring either directly or via a thio, sulfinyl, sulfonyl, carbonyl or oxycarbonyl group and optionally, a C1-4-alkylene bridge, particularly methylene; C2-6-alkenyl or -alkynyl, especially C2-3-alkenyl or -alkynyl each optionally substituted by one or more halogens; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl and phenyl and attached to the ring either directly or via a carbonyl group or a C1-4-alkylene bridge, particularly methylene; naphthyl; or phenyl, phenylalkyl or phenylalkenyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, C1-6-alkylthio, amino, azido, phenyl and nitro and each attached to the ring either directly or via an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally additionally a C1-4-alkylene bridge, particularly methylene.
Also, preferably, R3 is C1-6-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanato, azido, alkoxy, alkylthio, phenylsulfonyl; nitrooxy; C2-3-alkenyl or -alkynyl each optionally substituted by one or more halogens or by acetyl; tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; or phenyl or phenylalkyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, amino, azido, phenyl and nitro and each attached to the ring either directly or via a sulfonyloxy and optionally additionally a C1-4-alkylene bridge, particularly methylene.
Other examples of preferred R3 groups are hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least one halogen atom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.
R3 is especially C1-4-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanato or azido; C2-5-alkenyl or -alkynyl, each optionally substituted by one or more halogens; thienyl; or phenyl optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl or azido.
Further examples of preferred R3 groups are C1-6 alkyl and C2-6 haloalkenyl.
Preferably R5 and R6 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, especially hydrogen or methyl.
Especially at least one and most preferably both of R5 and R6 are hydrogen.
Preferably R7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl or the same substituted by at least one halogen atom such as trifluoromethyl, chlorophenyl.
Preferably R7 is hydrogen, methyl or ethyl especially hydrogen.
Preferably R8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or the same substituted by at least one halogen atom such as trifluoromethyl, chlorobenzyl.
Preferably R8 is hydrogen or methyl.
Combinations of one or more of these preferred compound groups are especially preferred.
A particular group of compounds of formula I (Compounds 1A) comprises those wherein,
A2 is oxygen;
X is xe2x80x94CONR5R6 or xe2x80x94COOR7 or xe2x80x94COxe2x80x94R8 or CN;
R1 is hydrogen or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano;
R2, R3, R4, are the same or different and each is independently hydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, a sulfonyl derivative, a sulfinyl derivative, an amino derivative, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, a thio derivative, alkyl, alkoxy, oxyester, oxyamido, aryl, an oxy derivative, heterocycle, vinyl and R3 may additionally represent C2-5 alkenyl, C2-5 alkynyl or azido each optionally substituted by one or more halogen, cyano, thiocyano, azido, cyclopropyl, acyl and/or phenyl; or phenylsulfonyloxy whereby any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl; most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
R2a, R3a and R4a are hydrogen R5, R6, R7 are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycle or oxy derivative; and
R8 is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle, alkylthio or thio derivative.
Within these Compounds 1A, R1 is preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl; most preferably methyl, ethyl or n-propyl.
R2 and R4 are preferably independently hydrogen or halogen or methyl, ethyl, propyl, isopropyl, butyl, isobutyl; and, most preferably, are each hydrogen.
R3 is preferably C1-5 alkyl, C2-5 alkenyl, C2-C5 alkynyl, cyclopropyl, azido, each optionally substituded by one or more halogen, cyano, thiocyano, azido, alkylthio, cyclopropyl, acyl and/or phenyl; phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl, pyrrole, pyridine, whereby any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl; most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
X is preferably xe2x80x94COOH or xe2x80x94COOMe or xe2x80x94COOEt or xe2x80x94CONH2; most preferably xe2x80x94CONH2.
A further particular group of compounds of formula I (Compounds 1B) comprises those wherein,
X is xe2x80x94CA1NH2, xe2x80x94CA1NHCH3 or xe2x80x94CA1N(CH3)2;
R1 is alkyl or phenyl;
R3 is alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl, amido, aryl, heterocycle; or
R3 is CH2R10 wherein R10 is hydrogen, cycloalkyl, oxyester, oxyalkylsulfonyl, oxyarylsufonyl, aminoalkylsulfonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy or trifluoroethyl;
R3a is hydrogen, alkyl or aryl (especially with the proviso that when R3a is hydrogen, R3 other than methyl);
or R3R3a form a cycloalkyl;
and R2, R2a, R4 and R4a are each hydrogen.
Within the compounds of formula I,
R1 is preferably alkyl especially C1-12- more particularly C1-6-alkyl and is most preferably ethyl;
R2, R2a, R3a and R4a are preferably hydrogen;
R3 is preferably selected from hydrogen; C1-12-alkyl, especially C1-6-alkyl, each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ring either directly or via a thio, sulfinyl, sulfonyl, carbonyl or oxycarbonyl group and optionally additionally a C1-4-alkylene bridge, particularly methylene; C2-6-alkenyl or -alkynyl, especially C2-3-alkenyl or -alkynyl, each optionally substituted by one or more halogens; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl and phenyl and attached to the ring either directly or via a carbonyl group or a C1-4-alkylene bridge, particularly methylene; naphthyl; or phenyl, phenylalkyl or phenylalkenyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, C1-6-alkylthio, amino, azido, phenyl and nitro and each attached to the ring either directly or via an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally additionally a C1-4-alkylene bridge, particularly methylene;
R3a is preferably hydrogen or C1-4-alkyl;
R4 and R4a are preferably, independently hydrogen, C1-4-alkyl, phenyl or benzyl.
A further group of compounds of formula I (Compounds IC) comprises those in racemic form wherein, when X is xe2x80x94CONR5R6 and R1 is hydrogen, methyl, ethyl or propyl, then substitution on the pyrrolidine ring is other than mono-, di-, or tri-methyl or mono-ethyl.
A further group of compound of formula I (Compounds 1D) comprises those in racemic form wherein, when X is xe2x80x94CONR5R6 and R1 is hydrogen or C1-6-alkyl, C2-6-alkenyl or -alkynyl or cycloalkyl, each unsubstituted, then substitution in the ring is other than by alkyl, alkenyl or alkynyl, each unsubstituted.
A further particular group of compounds of formula I (Compounds IE) comprises those wherein,
X is xe2x80x94CA1NH2;
R1 is H;
R3 is azidomethyl, iodomethyl, ethyl optionally substituted by 1 to 5 halogen atoms, n-propyl optionally substituted by 1 to 5 halogen atoms, vinyl optionally subsituted by one or two methyl, and/or 1 to 3 halogen atoms, acetylene optionally substituted by C1-4-alkyl, phenyl or halogen;
R3a is hydrogen or halogen, preferably fluorine;
and R2, R2a, R4 and R4a are each hydrogen; as their racemates or in enantiomerically enriched form, preferably the pure enantiomers.
A further particular group of compounds of formula I (Compounds 1F) comprises those wherein,
X is xe2x80x94CA1NH2;
R1 is H;
R3 is C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl optionally substituted by azido, oxynitro, 1 to 6 halogen atoms;
R3a is hydrogen or halogen, preferably fluorine;
and R2, R2a, R4 and R4a are each hydrogen; as their racemates or in enantiomerically enriched form, preferably the pure enantiomers.
In all the above mentioned scopes when the carbon atom to which R1 is attached is asymmetric it is preferably in the xe2x80x9cSxe2x80x9d-configuration.
The xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d according to the invention include therapeutically active, non-toxic base and acid salt forms which the compounds of formula I are able to form.
The acid addition salt form of a compound of formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like.
The compounds of formula I containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt forms, e.g. metal or amine salts, by treatment with appropriate organic and inorganic bases. Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e.g. lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Conversely said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
Compounds of the formula I and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like.
Many of the compounds of formula I and some of their intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondance with the rules described in Pure Appl. Chem., 45 (1976) 11-30.
The invention also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds of formula I or mixtures thereof (including all possible mixtures of stereoisomers).
Furthermore certain compounds of formula I which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the invention includes both mixture and separate individual isomers.
Multiple substituents on the pyrrolidone ring can also stand in either cis or trans relationship to each other with respect to the plane of the pyrrolidone ring.
Some of the compounds of formula I may also exist in tautomeric forms. Such forms although not explicity indicated in the above formula are intended to be included within the scope of the present invention.
With respect to the present invention reference to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically.
The invention also includes within its scope pro-drug forms of the compounds of formula I and its various sub-scopes and sub-groups.
The term xe2x80x9cprodrugxe2x80x9d as"" used herein includes compound forms which are rapidly transformed in vivo to the parent compound according to the invention, for example, by hydrolysis in blood. Prodrugs are compounds bearing groups which are removed by biotransformation prior to exhibiting their pharmacological action. Such groups include moieties which are readily cleaved in vivo from the compound bearing it, which compound after cleavage remains or becomes pharmacologically active. Metabolically cleavable groups form a class of groups well known to practitioners of the art. They include, but are not limited to such groups as alkanoyl (i.e. acetyl, propionyl, butyryl, and the like), unsubstituted and substituted carbocyclic aroyl (such as benzoyl, substituted benzoyl and 1- and 2-naphthoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialklysilyl (such as trimethyl- and triethylsilyl), monoesters formed with dicarboxylic acids (such as succinyl), phosphate, sulfate, sulfonate, sulfonyl, sulfinyl and the like. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. T. Higuchi and V. Stella, xe2x80x9cPro-drugs as Novel Delivery Systemxe2x80x9d, Vol. 14 of the A.C.S. Symposium Series; xe2x80x9cBioreversible Carriers in Drug Designxe2x80x9d, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
The compounds of formula I according to their invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry.
The following process description sets forth certain synthesis routes in an illustrative manner. Other alternative and/or analogous methods will be readily apparent to those skilled in this art. As used herein in connection with substituent meanings, xe2x80x9c=xe2x80x9d means xe2x80x9cisxe2x80x9d and xe2x80x9cxe2x89xa0xe2x80x9d means xe2x80x9cis other thanxe2x80x9d.
A. Cyclisation of an Aminoester
When, in formula I, A2=O, an aminoester of formula AA-II is cyclised wherein Q1, together with the oxygen to which it is attached, is a leaving group, especially Q1 is an alkyl group, in particular a linear or branched alkyl group having 1 to 4 carbon atoms. 
Q1=methyl or ethyl. The reaction is known per se and is generally carried out between room temperature and 150xc2x0 C., in the presence or not of a catalyst such as acetic acid, hydroxybenzotriazole or 2-hydroxypyridine.
Q1xe2x89xa0methyl or ethyl. Ester of formula AA-II is hydrolysed under acidic or basic conditions then cyclised under conventional peptide synthesis conditions, by using coupling agents, for example dicyclohexylcarbodiimide (Bodanszky, M., Bodanszky, A., in xe2x80x9cThe Practice of Peptide Synthesisxe2x80x9d, Springer Verlag, 1984).
A.1 Synthesis of AA-II by Addition on an Itaconate Derivative
Compounds of formula AA-II wherein R2a=R3a=H and R3=COOQ2, wherein Q2 represents a linear or branched alkyl group optionally optically active, are obtained by reaction of a compound of formula AA-III with an itaconate derivative of formula AA-IV according to the equation: 
This reaction may be performed according to the procedure described in: Street, L. J., Baker, R., Book, T., Kneen, C. O., ManLeod, A. M., Merchant, K. J., Showell, G. A., Saunders, J., Herbert, R. H., Freedman, S. B., Harley, E. A., J. Med. Chem. (1990), 33, 2690-2697.
A.2 Synthesis of AA-II by Reductive Amination
A compound of formula AA-II may be prepared by reductive amination of a compound of formula AA-V with a compound of formula AA-III according to the equation: 
This reaction may be carried out using the conditions described in Abdel-Magid, A. F., Harris, B. D., Maryanoff, C. A., Synlett (1994), 81-83. Alternatively, when X represents CONR5R6, the amine AA-III may be linked via the amide moiety onto a solid support (for example a Rink resin).
Compounds of formula AA-V may be prepared by one of the following processes: 
A.2.1. An aldehyde of formula AA-VI is alkylated with an alkyl halogenoacetate of formula AA-VII, wherein X1 represents a halogen atom, using intermediate enamines as described in Whitessell, J. K., Whitessell, M. A., Synthesis, (1983), 517-536 or using hydrazones as described in Corey, E. J., Enders, D., Tetrahedron Lett. (1976), 11-14 followed by ozonolysis.
A2.2. A nitroester of formula AA-VIII may be transformed into the compound AA-V by treatment of its conjugate base with sulfuric acid in methanol and hydrolysis of the intermediate dimethylacetal (Nef reaction as in Urpi, F., Vilarrasa, J., Tetrahedron Lett. (1990), 31, 7499-7500). The nitroester of formula AA-VIII may be prepared as described in Horni, A., Hubacek, I., Hesse, M., Helv. Chim. Acta (1994), 77, 579.
A.2.3. An ester AA-X is alkylated by an allyl halide AA-IX (X1=halogen atom) in the presence of a strong base (for example lithium diisopropylamide), followed by reductive ozonolysis of the unsaturated ester as described in Amruta Reddy P., Hsiang B. C. H., Latifi T. N., Hill M. W., Woodward K. E., Rothman S. M., Ferrendelli J. A., Covey D. F., J. Med. Chem. (1996), 39, 1898-1906.
A.3. Synthesis of AA-II by Alkylation of a xcex3-Halogeno Ester
A compound of formula AA-II wherein X=CONR5R6, COOR7 or CN may be prepared by alkylation of a xcex3-halogeno ester AA-XI, wherein X2 represents a halogen atom, with an amine AA-III. 
This reaction may be carried out using the conditions described in Patent Application GB 2225322 A. The synthesis of the ester AA-XI is described in part B.
A.4. Synthesis of AA-II by Reductive Amination of 5-Hydroxylactone Derivatives
A compound of formula AA-II wherein X=CONR5R6, COOR7 or CN, Q1=H and R2a=H may be prepared by reductive amination of a 5-hydroxylactone of formula AA-XII with an amine of formula AA-III according to the equation: 
The 5-hydroxylactone of formula AA-XII may be synthesised as described in B.1.
B. Condensation of an Amine with a xcex3-Halogeno Acid Derivative
When, in formula I, A2=O, X=CONR7R8, COOR7 or CN and R2a=H, a compound of formula AA-XIII is reacted with an amine of formula AA-III according to the equation: 
wherein X3 represents a halogen atom, preferably an iodine or a chlorine atom, X4 represents a halogen atom, preferably a chlorine atom. This reaction may be carried out as described in patent application GB 2225322 A.
Compounds formula AA-XIII may be obtained by the opening of a lactone of formula AA-XIV in the presence of an halogenation agent, for example TMSI, SOCl2/ZnCl2 (followed if necessary by halogenation of the obtained halogeno acid (X4=OH)) according to the equation: 
Opening of the lactone AA-XIV can be performed according to the procedure described in: Mazzini, C., Lebreton, J., Alphand, V., Furstoss, R., Tetrahedron Lett. (1998), 38, 1195-1196 and in Olah, G. A., Narang, S. C., Gupta, B. G. B., Malhotra, R., J. Org. Chem. (1979), 44, 1247-1250. Halogenation (X4=halogen) or esterification (X4=OQ1) of the obtained halogeno acid (X4=OH) may be performed under any conditions known to the person skilled in the art. Lactones of formula AA-XIV may be prepared by one of the following processes:
B.1. Hydrogenation or Conjugated Addition of an Organometallic
Compound AA-XIV wherein R2a=R4a=H may be obtained hydrogenation of an xcex1,xcex2-unsaturated lactone of formula AA-XV, or by conjugated addition of an organometallic derivative of formula R3M, wherein M represents Li, Na, Mg or Zn, onto compound AA-XV eventually catalysed by Copper (I) salts. 
This reaction may be carried out according to the procedures described in: Alexakis, A., Berlan, J., Besace, Y., Tetrahedron Lett. (1986), 27, 1047-1050; Lipshutz, B. H., Ellsworth, E. L., Siahaan, T., J. Amer. Chem. Soc. (1989), 111, 1351-1358, or under any condition known to the person skilled in the art.
B.2 Reduction of a Succinate Derivative
When, in formula AA-XIV, R2=R2a=H: reduction of the carboxylic acid AA-XVI in the presence of a borohydride reagent, preferably LiBH4 or Ca(BH4)2, in an alcoholic solvent, according to the equation: 
wherein Q3 is a methyl or an ethyl group, G1 represents O or S and Q4 represents an hydrogen atom or a linear or branched alkyl having 1 to 4 atoms of carbon, with the condition that when G1=S, Q4=alkyl and when G1=O, Q4=H.
C. Alkylation of a Lactam Derivative
When, in formula I, A2=O and X=COOR7, a compound of formula AA-XVII is reacted with a compound of formula AA-XVIII according to the equation: 
wherein X5 represents a halogen atom and M an alkali metal. This reaction may be carried out following the procedure described in patent application GB [(case 15-09)]2225322A.
Compounds of formula AA-XVII may be prepared according to the procedure described in Horni, A., Hubacek, I., Hesse, M., Helv. Chim. Acta (1994), 77, 579.
D. Transformation of an Ester Derivative
When, in formula I, A2=O and X=CONR5R6, none of the groups R2, R2a, R3, R3a, R4 and R4a being substituted by carboxyl, ester or sulfonic acid, the corresponding ester of formula I 
wherein R7 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 atoms of carbon, is transformed into amine under direct ammonolysis or under conventional peptidic synthesis conditions by using an amine and coupling agents, for example alkyl chloroformate or dicyclohexylcarbodiimide.
E. Reduction of an xcex1,xcex2-unsaturated Lactam
When, in formula I, A2=O and R2a=R3a=R4a=H, compounds of formula I may be obtained by reduction of an unsaturated lactam AA-XIX: 
The reduction step may be performed under classical conditions known to the person skilled in the art, for example hydrogen in the presence of Pd/C or optionally in the presence of an optically active catalyst. When R2, R3 or R4 is susceptible to be hydrogenated under low pressure conditions, for example by using Pd/C as catalyst, the double bond of the olefin mixture may be reduced selectively with NaBH4 in the presence of CoCl2.
Compounds AA-XIX may be prepared by one of the following processes:
E.1 By Alkylation
A compound of formula AA-III is alkylated by a compound of formula AA-XX, wherein Q5 represents a linear or branched alkyl group having 1 to 4 atoms of carbon, and cyclised. The alkylation step may be carried out in an inert solvent, for example tetrahydrofuran, dimethylformamide or dichloromethane, between 0 and 50xc2x0 C., in the presence or not of a tertiary amine. The cyclisation reaction may occur spontaneously or may be carried out according to the method described in part A.
E.2 By Reductive Amination
A compound of formula AA-III is reacted with a compound of formula AA-m under reductive amination conditions. The first step of this reaction may be carried out in an inert solvent, for example toluene, between 0 and 50xc2x0 C., in the presence of a reducing agents such as NaBH3CN and in the presence of an acid, for example acetic acid. The synthesis of compounds AA-XXI is described in Bourguignon, J. J. et al., J. Med. Chem. (1988), 31, 893-897.
F. Functional Group Transformation of the Side Chain
F.1 Reduction of Esters into Alcohols
Compounds of formula I wherein A2=O, X=CONR5R6 or COOR7, R7 being a tertiary alkyl group, and one of the groups R2, R2a, R3, R3a, R4 and R4a represents -G2xe2x80x94COOQ6, G2 being a bond or an alkylene group and Q6 being a linear or branched alkyl group having 1 to 4 atoms of carbon, are key synthesis intermediates for corresponding compounds wherein one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94CH2OH. These transformations may be performed under any conditions known to the person skilled in the art.
F.2 Activation and Oxidation of Alcohols
Compounds of formula I wherein A2=O and one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94CH2OH, G2 being a bond or an alkylene group, are key synthesis intermediates for corresponding compounds wherein one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94CH2X6 or xe2x80x94G2xe2x80x94CHO wherein X6 represents a chlorine, a bromine or a iodine atom or a group of formula xe2x80x94Oxe2x80x94SO2xe2x80x94Q7 or xe2x80x94O xe2x80x94Q8, Q7 being an alkyl or an aryl group and Q8 being an alkyl group. These transformations may be performed under any conditions known to the person skilled in the art.
F.3 Nucleophilic Substitution of Activated Alcohols
Compounds of formula I wherein A2=O and one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94CH2X6, G2 being a bond or an alkylene group and X6 being a chlorine, a bromine or a iodine atom or a group of formula xe2x80x94Oxe2x80x94SO2xe2x80x94Q7 as defined in F.2, are key synthesis intermediates for corresponding compounds wherein one of the groups R2, R2a, R3, R3a, R4 and R4a represents G2xe2x80x94CH2X7, wherein X7 represents azido, halogen, nitro, amino, amino derivatives, thio derivatives and heterocycles. These transformations may be performed under any conditions known to the person skilled in the art.
F.4 By Olefination of an Aldehyde
Compounds of formula I wherein A2=O, X=CONR5R6, COOR7 or CN, and one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94CHO, G2 being a bond or an alkylene group, are key synthesis intermediates for corresponding compounds wherein one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94Q9 wherein Q9 represents a vinyl group not substituted, mono- or di-substituted by a halogen atom or an alkyl group. These transformations may be performed under any conditions known to the person skilled in the art.
Alternatively, compounds xe2x80x94G2xe2x80x94CN can be obtained from the corresponding aldehyde by reaction of its oxime with SeO2 (as described in Earl, R. A., Vollhardt, K. P. C., J. Org. Chem. (1984), 49, 4786).
F.5 Transformation of an Acid Derivative into Heterocycles
Compounds of formula I wherein A2=O and one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94CN or xe2x80x94G2xe2x80x94COQ10, G2 being a bond or an alkylene group and Q10 being an alkoxy, an aryloxy or an amino group, a halogen atom or an amino derivative, with the proviso that xe2x80x94COQ10 is different from X, are key synthesis intermediates for corresponding compounds wherein one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2-Q10 wherein Q11 represents either (i) a xe2x80x94COxe2x80x94aryl/heterocycle by palladium catalysed coupling between an acid chloride xe2x80x94G2xe2x80x94COCl and an aryl/heterocyclic organometallic, for example a trimethyl-pyridyl-stannane or (ii) an heterocycle, for example a thiazole (in Friedman, B. S., Sparks, M., Adams, R., J. Amer. Chem. Soc. (1933), 55, 2262 or in Iroka, N., Hamada, Y., Shiori, T., Tetrahedron (1992), 48, 7251), an oxazole (in Street, L. J., Baker, R., Castro, J. L., Clamber, R. S., Guiblin, A. R., Hobbs, S. C., Metassa, V. G., Reeve, A. J., Beer, M. S., Middlemis, D. N., Noble, A. J., Stanton, J. A., Scholey, K., Hargreaves, R. J., J. Med. Chem. (1993), 36, 1529), an oxadiazole (Ainsworth, C., J. Amer. Chem. Soc. (1955), 77, 1148), a tetrazole starting from a nitrile (Goerlitzer, K., Kogt, R., Arch. Pharm. (1990), 323, 847) or a thiadiazole (Lamattina, J. L., Mularski, C. J., J. Org. Chem. (1984), 49, 4800).
F.6 Synthesis of Ketone Derivatives
Compounds of formula I wherein A2=O, and one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94CH=CQ12Q13 or xe2x80x94G2xe2x80x94CQ13=CHQ12, G2 being a bond or an alkylene group, Q12 and Q13 being a hydrogen atom or an alkyl group, with the proviso that none of the other R1, X, R2, R2a, R3, R3a, R4 and R4a is bearing a functional group sensible to oxidising conditions, are key synthesis intermediates for corresponding compounds wherein one of the groups R2, R2a, R3, R3a, R4 and R4a represents respectively xe2x80x94G2xe2x80x94COxe2x80x94CHQ12Q13 or xe2x80x94G2xe2x80x94CHQ13xe2x80x94COxe2x80x94Q12.
These transformation may be performed under any appropriate conditions known to the person skilled in the art, for example in presence of O2 and PdCl2, in an inert solvent, for example dimethylformamide or N-methylpyrrolidine, between 0 and 50xc2x0 C. (Bird, Transition Metals Intermediate in Organic Synthesis,Academic Press, NY, (1967), 88-111).
F.7 Derivatisation of Ketones
Compounds of formula I wherein A2=O, X=CONR5R6 or COOR7 and one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94CO xe2x80x94Q14, wherein G2 is a bond an alkylene group and Q14 represents an alkyl group, are key synthesis intermediates for the synthesis of (i) alcohols xe2x80x94G2xe2x80x94CHOHxe2x80x94Q14 by reduction with an hydride reagent ((March, J., Advanced Organic Chemistry, Third Edition,John Wiley and Sons, (1985), 809), (ii) fluorinated side chain xe2x80x94G2xe2x80x94CF2xe2x80x94Q14 using the conditions described in Lal, G. S., Pez, G. P., Pesaresi, R. J., Prozonic, F. M., Chem. Commun. (1999), 215-216.
F.8 Synthesis of Alkynyl Derivatives
Compounds of formula I wherein A2=O and one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94Cxe2x95x90C(X8)2, G2 being a bond or an alkylene group and X8 being a halogen atom, with the proviso that none of the other X, R1, R2, R2a, R3, R3a, R4 and R4a is bearing a functional group sensible sensitive to strong bases, are key synthesis intermediates for corresponding compounds wherein one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94Cxe2x89xa1Cxe2x80x94Q15, wherein Q15 is hydrogen, halogen, alkyl or aryl.
These transformation may be performed:
by base induced xcex2-elimination (for example 1 equivalent of t-BuOK at low temperature as described in Michel, P., Rassat, A., Tetrahedron Lett. (1999), 40, 8579-8581) into an haloacetylenic derivative (Q15=halogen) followed by metal catalysed substitution of the halogen by an organometallic species (for example by MeZnCl in the presence of CuCN.LiCl as described in Micouin, L., Knochel, P., Synlett (1997), 327),
by direct conversion into a metal acetylenide (for example with 2 equiv. of n-butyllithium) and alkylation with an alkylhalide or a carbonyl derivative (as described in Corey, E. J., Fuchs, P. L., Tetrahedron Lett. (1972), 36, 3769-3772).
F.9 Synthesis of Alkanes
Compounds of formula I wherein A2=O and one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94Cxe2x95x90Cxe2x80x94Q16Q17, G2 being a bond or an alkylene group, Q16 and Q17 being alkyl or fluoro, are key synthesis intermediates for corresponding compounds wherein one of the groups R2, R2a, R3, R3a, R4 and R4a represents xe2x80x94G2xe2x80x94CHxe2x80x94CHxe2x80x94Q16Q17.
The reduction step may be performed under classical conditions known to the person skilled in the art, for example with hydrogen in the presence of Pd/C (March, J., xe2x80x9cAdvanced Organic Chemistry, Third Editionxe2x80x9d, John Wiley and Sons, (1985), 1101-1102).
F.10 Synthesis of (Halo)azidoaryl Derivatives
Compounds of formula I wherein A2=O, X=CONR5R6 or COOR7 or CN and one of the groups R2, R3 or R4 is G2xe2x80x94Q18 wherein Q18 represents a nitroaryl or triazenoaryl, G2 being a bond or an alkylene group, are key intermediates for the synthesis of corresponding compounds wherein one of the groups R2, R3 or R4 is G2xe2x80x94Q19, Q19 being an azidoaryl optionally substituted by one or several halogen atoms, preferably Br or F atoms. The transformation proceeds through the reduction of the nitro or triazene moiety into aniline by any means known by persons skilled in the art, optionally introduction of one or several halogen atoms (as in Xing-teng, D., Guo-bin, L., Synth. Commun. (1989), 19, 1261) and conversion of the amine into azide by well known methods.
F.11 Synthesis of Heterocycles from Amines
Compounds of formula I wherein A1=O, X=CONR5R6, COOR7 or CN, and one of the groups R2, R3 or R4 is G2xe2x80x94Q20, wherein G2 being a bond or an alkylene group and Q20 is COOH, CONH2 or CN, are key intermediates for the synthesis of corresponding compounds wherein one of the groups R2, R3 or R4 is G2xe2x80x94NH2 or G2xe2x80x94CH2xe2x80x94NH2, which lead to corresponding compounds wherein one of the groups R2, R3 or R4 is G2xe2x80x94Het or G2xe2x80x94CH2xe2x80x94Het, where Het is an heterocycle bound by a nitrogen atom, optionally substituted by one or several halogen atoms.
In the case where X=CONR5R6, CN or COOR7 with R7 different from H, and where R2, R3 or R4 is G2xe2x80x94COOH, the transformation proceeds through Curtius rearrangement (for example by action of diphenylphosphorazidate and triethylamine and quenching in situ by benzyl alcohol as described in: Kim, D., Weinreb, S. M., J. Org. Chem. (1978), 43, 125), deprotection of the amine function by hydrogenolysis or any condition known to the person skilled in the art to give R2, R3 or R4=G2xe2x80x94NH2, followed by ring synthesis to give an heterocycle such as a pyrrole (as in Jefford, C. W., Tang, Q., Zaslona, A., J. Amer. Chem. Soc. (1991), 113, 3513-3518), and optionally introduction of one or several halogen atoms on the ring (as in Gilow, H. M., Burton, D. E., J. Org. Chem. (1981), 46, 2221-2225).
In the case where X=CONR5R6, COOR7 or CN and one of the groups R2, R3 or R4 is G2xe2x80x94CONH2, with X different from CONR5R6, or G2xe2x80x94CN, with X different from CN, the transformation proceeds through selective reduction of the amide or nitrile into the aminomethyl moiety under any condition known to the person skilled in the art, and ring synthesis to give an heterocycle such as a triazole (as in Miles, R. W., Samano, V., Robins, M. J., J. Amer. Chem. Soc. (1995), 117, 5951-5957).
F.12 Synthesis of Triazoles
Compounds of formula I wherein A2=O and one of the groups R2, R2a, R3, R3a, R4 and R4 represents xe2x80x94G2xe2x80x94CH2N3, G2 being a bond or an alkylene group, are key synthesis intermediates for corresponding compounds wherein one of the groups R2, R2a, R3, R3a, R4 and R4 represents xe2x80x94G2xe2x80x94CH2-triazole. These transformations may be performed by prolonged heating in the presence of 1-(triphenylphosphoranylidene)-ketone derivative (as described in Hammerschmidt, F., Polsterer, J. P., Zbiral, E., Synthesis (1995), 415).
F.13 Resolution
When compounds of formula I present one or several stereogenic centres, and that non-stereoselective methods of synthesis are used, resolution of the mixture of stereoisomers can best be effected in one or several steps, involving generally sequential separation of mixtures of diastereomers into their constituting racemates, using preferably chromatographic separations on achiral or chiral phase in reversed or preferably in direct mode, followed by at least one ultimate step of resolution of each racemate into its enantiomers, using most preferably chromatographic separation on chiral phase in reversed or preferably in direct mode. Alternatively, when partly stereoselective methods of synthesis are used, the ultimate step may be a separation of diastereomers using preferably chromatographic separations on achiral or chiral phase in reversed or preferably in direct mode.
Certain of the intermediate compounds described above particularly those of formula AA-II wherein the various substituents have the meanings set forth above are novel and also form part of the invention. These novel intermediates, wherein the leaving group is pharmaceutically acceptable, possess the same utility as described for the compounds of formula I hereunder.
It has now been found that compounds of formula I and their pharmaceutically acceptable salts are useful in a variety of pharmaceutical indications.
For example, the compounds according to the invention are useful for the treatment of epilepsy, epileptogenesis, seizure disorders and convulsions.
These compounds may also be used for the treatment of other neurological disorders including bipolar disorders, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, essential tremor and other movement disorders, neonatal cerebral haemorrhage, amyotrophic lateral sclerosis, spasticity, Parkinson""s disease and other degenerative diseases.
In addition the compounds according to the invention may be used in the treatment of bronchial asthma, asthmatic status and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis.
Thus, the present invention, in a further aspect, concerns the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of neurological and other disorders such as mentioned above.
In particular, the present invention concerns the use of a compound of formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of epilepsy, bipolar disorders, chronic pain or neuropathic pain, migraine, bronchial-, asthmatic- or allergic conditions.
The activity and properties of the active compounds, oral availability and stability in vitro or in vivo can vary significantly among the optical isomers of the disclosed compounds.
In a preferred embodiment, the active compound is administered in an enantiomerically enriched form, i.e., substantially in the form of one isomer.
For example, in the case of the compound of formula I wherein R1 is ethyl, X is xe2x80x94CONH2, A2 is oxygen, when R is propyl and all remaining substituents are hydrogen, it is the S (butanamide), R (ring) enantiomer which is preferred and when R3 is 2,2-difluorovinyl and all remaining substituents are hydrogen, it is the S (butanamide), S (ring) enantiomer which is preferred.
The present invention also concerns a method for treating epilepsy, migraine, bipolar disorders, chronic pain or neuropathic pain or bronchial-, asthmatic- or allergic conditions, in a mammal in need of such treatment, comprising administering a therapeutic dose of at least one compound of formula I or a pharmaceutically acceptable salt thereof to a patient.
The methods of the invention comprise administration to a mammal (preferably human) suffering from above mentioned conditions or disorders, of a compound according to the invention in an amount sufficient to alleviate or prevent the disorder or condition.
The compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 5 to 1000 mg, preferably 25 to 500 mg of active ingredient per unit dosage form.
The term xe2x80x9ctreatmentxe2x80x9d as used herein includes curative treatment and prophylactic treatment.
By xe2x80x9ccurativexe2x80x9d is meant efficacy in treating a current symtomatic episode of a disorder or condition.
By xe2x80x9cprophylacticxe2x80x9d is meant prevention of the occurrence or recurrence of a disorder or condition.
The term xe2x80x9cepilepsyxe2x80x9d as used herein refers to a disorder of brain function characterised by the periodic and unpredictable occurrence of seizures. Seizures can be xe2x80x9cnonepilepticxe2x80x9d when evoked in a normal brain by treatments such as electroshock or chemical convulsants or xe2x80x9cepilepticxe2x80x9d when evoked without evident provocation.
The term xe2x80x9cseizurexe2x80x9d as used herein refers to a transient alteration of behaviour due to the disordered, synchronous, and rhythmic firing of populations of brain neurones.
The term xe2x80x9cmigrainexe2x80x9d as used herein means a disorder characterised by recurrent attacks of headache that vary widely in intensity, frequency, and duration. The attacks are commonly unilateral and are usually associated with anorexia, nausea, vomiting, phonophobia, and/or photophobia. In some cases they are preceded by, or associated with, neurological and mood disturbances. Migraine headache may last from 4 hours to about 72 hours. The International Headache Society (1HS, 1988) classifies migraine with aura (classical migraine) and migraine without aura (common migraine) as the major types of migraine. Migraine with aura consists of a headache phase preceded by characteristic visual, sensory, speech, or motor symptoms. In the absence of such symptoms, the headache is called migraine without aura.
The term xe2x80x9cbipolar disordersxe2x80x9d as used herein refers to those disorders classified as Mood Disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (Diagnostic and Statistical Manual of Mental Disorders (DSM-IV TM), American Psychiatry Association, Washington, D.C., 1994). Bipolar disorders are generally characterised by spontaneously triggered repeated (i.e. at least two) episodes in which the patient""s hyperexcitability, activity and mood are significantly disturbed, this disturbance consisting on some occasions of an elevation of mood and increased energy and activity (mania or hypomania), and in other occasions a lowering of mood and decreased energy and activity (depression). Bipolar disorders are separated into four main categories in the DSM-IV (bipolar I disorder, bipolar II disorder, cyclothymia, and bipolar disorders not otherwise specified).
The term xe2x80x9cmanic episodexe2x80x9d, as used herein refers to a distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood with signs of pressured speech and psychomotor agitation.
The term xe2x80x9chypomaniaxe2x80x9d, as used herein refers to a less extreme manic episode, with lower grade of severity.
The term xe2x80x9cmajor depressive episodexe2x80x9d, as used herein refers to a period of at least 2 weeks during which there is either depressed mood or the loss of interest or pleasure in nearly all activities with signs of impaired concentration and psychomotor retardation.
The term xe2x80x9cmixed episodexe2x80x9d, as used herein refers to a period of time (lasting at least 1 week) in which the criteria are met both for a manic episode and for a major depressive episode nearly every day.
The term xe2x80x9cchronic painxe2x80x9d as used herein refers to the condition gradually being recognised as a disease process distinct from acute pain. Conventionally defined as pain that persists beyond the normal time of healing, pain can also be considered chronic at the point when the individual realises that the pain is going to be a persistent part of their lives for the foreseeable future. It is likely that a majority of chronic pain syndromes involves a neuropathic component, which is usually harder to treat than acute somatic pain The term xe2x80x9cneuropathic painxe2x80x9d as used herein refers to pain initiated by a pathological change in a nerve which signals the presence of a noxious stimulus when no such recognisable stimulus exists, giving rise to a false sensation of pain. In other words, it appears that the pain system has been turned on and cannot turn itself off.
The activity of the compounds of formula I, or their pharmaceutically acceptable salts, as anticonvulsants can be determined in the audiogenic seizures model. The objective of this test is to evaluate the anticonvulsant potential of a compound by means of audiogenic seizures induced in sound-susceptible mice, a genetic animal model with reflex seizures. In this model of primary generalised epilepsy, seizures are evoked without electrical or chemical stimulation and the seizure types are, at least in part, similar in their clinical phenomenology to seizures occurring in man (Lxc3x6scher W. and Schmidt D., Epilepsy Res. (1998), 2, p. 145-181; Buchhalter J. R., Epilepsia (1993), 34, S31-S41). Results obtained with compounds of formula I are indicative of a strong pharmacological effect.
Another assay indicative of potential anticonvulsant activity is binding to levetiracetam binding site (LBS) as hereinafter described.
The activity of the compounds of formula I, or their pharmaceutically acceptable salts, in chronic neuropathic pain can be determined in animal models. For example, chronic neuropathic pain can be modelled by pharmacologically inducing diabetes in rats. In this model, animals show progressive hyperalgesia to nociceptive stimuli, a symptom generally observed in patients with painful peripheral neuropathy (Courteix C, Eschalier, A. and Lavarenne J., Pain, 53,(1993) 81-88). This model was shown to possess a high pharmacological predictivity.(Courteix C, Bardin M., Chantelauze C., Lavarenne J and Eschalier, A., Pain, 57 (1994) 153-160)
The activity of the compounds of formula I, or their pharmaceutically acceptable salts, in bipolar disorders can be assessed in animal models. For example, bipolar disorders and especially mania can be modelled by pharmacologically inducing hyperactivity in rats and evaluating their behaviour in a Y maze. In such a situation, therapeutic agents effective in man, like Lithium and sodium valproate decrease the hyperactivity, thus validating the predictivity of the model (Cao B. J., and Peng N; A;, Eur. J; Pharmacol. 237 (1993) 177-181. Vale A. L. and Ratcliffe F. Psychopharmacology, 91 (1987) 352-355).
Potential anti-asthmatic properties of the compounds of formula I, or their pharmaceutically acceptable salts would be tested for in an animal model of allergic asthma, in which guinea pigs sensitised to ovalbumin are challenged with the antigen and investigated for changes in pulmonary function and airway inflammatory cell content. (Yamada et al. (1992) Development of an animal model of late asthmatic response in guinea pigs and effects anti-asthmatic drugs. Prostaglandins, 43: 507-521).
Activity in any of the abovementioned indications can of course be determined by carrying out suitable clinical trials in a manner known to a person skilled in the relevant art for the particular indication and/or in the design of clinical trials in general.
For treating diseases, compounds of formula I or their pharmaceutically acceptable salts, may be employed at an effective daily dosage and administered in the form of a pharmaceutical composition.
Therefore, another embodiment of the present invention concerns a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.
To prepare a pharmaceutical composition according to the invention, one or more of the compounds of formula I or a pharmaceutically acceptable salt thereof, is intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to the skilled practitioner.
Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, e.g., oral, rectal, or parenteral.
Pharmaceutical compositions comprising compounds according to the invention can, for example, be administered orally or parenterally, i.e., intravenously, intramuscularly or subcutaneously, intrathecally.
Pharmaceutical compositions suitable for oral administration can be solids or liquids and can, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, and the like.
To this end the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose. Optionally, these pharmaceutical compositions can also contain a binder such as microcrystalline cellulose, gum tragacanth or gelatine, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or colouring agents or a flavouring agent such as peppermint or methyl salicylate.
The invention also contemplates compositions which can release the active substance in a controlled manner. Pharmaceutical compositions which can be used for parenteral administration are in conventional form such as aqueous or oily solutions or suspensions generally contained in ampoules, disposable syringes, glass or plastics vials or infusion containers.
In addition to the active ingredient, these solutions or suspensions can optionally also contain a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting the osmolarity, such as sodium chloride or dextrose.
These pharmaceutical forms are prepared using methods which are routinely used by pharmacists.
The amount of active ingredient in the pharmaceutical compositions can fall within a wide range of concentrations and depends on a variety of factors such as the patient""s sex, age, weight and medical condition, as well as on the method of administration. Thus the quantity of compound of formula I in compositions for oral administration is at least 0.5% by weight and can be up to 80% by weight with respect to the total weight of the composition.
In accordance with the invention it has also been found that the compounds of formula I or the pharmaceutically acceptable salts thereof can be administered alone or in combination with other pharmaceutically active ingredients. Non-limiting examples of such additional compounds which can be cited for use in combination with the compounds according to the invention are antivirals, antispastics (e.g. baclofen), antiemetics, antimanic mood stabilizing agents, analgesics (e.g. aspirin, ibuprofen, paracetamol), narcotic analgesics, topical anesthetics, opioid analgesics, lithium salts, antidepressants (e.g. mianserin, fluoxetine, trazodone), tricyclic antidepressants (e.g. imipramine, desipramine), anticonvulsants (e.g. valproic acid, carbamazepine, phenytoin), antipsychotics (e.g. risperidone, haloperidol), neuroleptics, benzodiazepines (e.g. diazepam, clonazepam), phenothiazines (e.g. chlorpromazine), calcium channel blockers, amphetamine, clonidine, lidocaine, mexiletine, capsaicin, caffeine, quetiapine, serotonin antagonists, xcex2-blockers, antiarrhythmics, triptans, ergot derivatives.
Of particular interest in accordance with the present invention are combinations of at least one compound of formula I or a pharmaceutically acceptable salt thereof and at least one compound inducing neural inhibition mediated by GABAA receptors. The compounds of formula I exhibit a potentiating effect on the compounds inducing neural inhibition mediated by GABAA receptors enabling, in many cases, effective treatment of conditions and disorders under reduced risk of adverse effects.
Examples of compounds inducing neural inhibition mediated by GABAA receptors include the following: benzodiazepines, barbiturates, steroids, and anticonvulsants such as valproate, viagabatrine, tiagabine or pharmaceutical acceptable salts thereof.
Benzodiazepines include the 1,4 benzodiazepines, such as diazepam and clonazepam, and the 1,5 benzodiazepines, such as clobazam. Preferred compound is clonazepam.
Barbiturates include phenobarbital and pentobarbital. Preferred compound is phenobarbital.
Steroids include adrenocorticotropic hormones such as tetracosactide acetate, etc.
Anticonvulsants include hydantoins (phenytoin, ethotoin, etc), oxazolidines (trimethadione, etc.), succinimides (ethosuximide, etc.), phenacemides (phenacemide, acetylpheneturide, etc.), sulfonamides (sulthiame, acetoazolamide, etc.), aminobutyric acids (e.g. gamma-amino-beta-hydroxybutyric acid, etc.), sodium valproate and derivatives, carbamazepine and so on.
Preferred compounds include valproic acid, valpromide, valproate pivoxil, sodium valproate, semi-sodium valproate, divalproex, clonazepam, phenobarbital, vigabatrine, tiagabine.
For the preferred oral compositions, the daily dosage is in the range 5 to 1000 milligrams (mg) of compounds of formula I.
In compositions for parenteral administration, the quantity of compound of formula I present is at least 0.5% by weight and can be up to 33% by weight with respect to the total weight of the composition. For the preferred parenteral compositions, the dosage unit is in the range 5 mg to 1000 mg of compounds of formula I.
The daily dose can fall within a wide range of dosage units of compound of formula I and is generally in the range 5 to 1000 mg. However, it should be understood that the specific doses can be adapted to particular cases depending on the individual requirements, at the physician""s discretion.
The amount of the active ingredients (compound I and compound inducing neural inhibition mediated by the GABAA receptors) in the pharmaceutical composition of the invention will vary depending on the mammal to which the compositions are administered, the disease to be treated, other active ingredients present, etc. Generally, the amount of the compound inducing neural inhibition mediated by the GABAA receptors and the amount of compound I for a given composition and dosage form can be readily determined employing routine procedures.
The following examples are provided for illustrative purposes only and are not intended, nor should they be construed, as limiting the invention in any manner. Those skilled in the art will appreciate that routine variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.
Unless specified otherwise in the examples, characterization of the compounds is performed according to the following methods:
NMR spectra are recorded on a BRUKER AC 250 Fourier Transform NMR Spectrometer fitted with an Aspect 3000 computer and a 5 mm 1H/13C dual probehead or BRUKER DRX 400 FT NMR fitted with a SG Indigo2 computer and a 5 mm inverse geometry 1H/13C/15N triple probehead. The compound is studied in DMSO-d6 (or CDCl3) solution at a probe temperature of 313 K and at a concentration of 20 mg/ml. The instrument is locked on the deuterium signal of DMSO-d6 (or CDCl3). Chemical shifts are given in ppm downfield from TMS taken as internal standard.
Mass spectrometric measurements in LC/MS mode are performed as follows:
HPLC Conditions
Analyses are performed using a WATERS Alliance HPLC system mounted with an IRTSEL ODS 3, DP 5 xcexcm, 250xc3x974.6 mm column.
The gradient ran from 100% solvent A (acetonitrile, water, TFA (10/90/0.1, v/v/v)) to 100% solvent B (acetonitrile, water, TFA (90/10/0.1, v/v/v)) in 7 min with a hold at 100% B of 4 min. The flow rate is set at 2.5 ml/min and a split of 1/10 is used just before API source. The chromatography is carried out at 30xc2x0 C.
MS Conditions
Samples are dissolved in acetonitrile/water, 70/30, v/v at the concentration of about 250 xcexcgr/ml. API spectra (+or xe2x88x92) are performed using a FINNIGAN (San Jose, Calif., USA) LCQ ion trap mass spectrometer. APCI source operated at 450xc2x0 C. and the capillary heater at 160xc2x0 C. ESI source operated at 3.5 kV and the capillary heater at 210 C.
Mass spectrometric measurements in DIP/EI mode are performed as follows: samples are vaporized by heating the probe from 50xc2x0 C. to 250xc2x0 C. in 5 min. EI (Electron Impact) spectra are recorded using a FINNIGAN (San Jose, Calif., USA) TSQ 700 tandem quadrupole mass spectrometer. The source temperature is set at 150xc2x0 C.
Specific rotation is recorded on a Perkin-Elmer MC241 or 341 polarimeter. The angle of rotation is recorded at 25xc2x0 C. on 1% solutions in MeOH. For some molecules, the solvent is CH2Cl2 or DMSO, due to solubility problems.
Water content is determined using a Metrohm microcoulometric Karl Fischer titrator.
Preparative chromatographic separations are performed on silicagel 60 Merck, particle size 15-40 xcexcm, reference 1.15111.9025, using in-house modified Jobin Yvon-type axial compression columns (80 mm i.d.), flow rates between 70 and 150 ml/min. Amount of silicagel and solvent mixtures as described in individual procedures.
Preparative Chiral Chromatographic separations are performed on a DAICEL Chiralpak AD 20 xcexcm, 100*500 mm column using an in-house build instrument with various mixtures of lower alcohols and C5 to C8 linear, branched or cyclic alkanes at xc2x1350 ml/min. Solvent mixtures as described in individual procedures.
Melting points are determined on a Bxc3xcchi 535 Totoli-type fusionometer, and are not corrected, or by the onset temperature on a Perkin Elmer DSC 7:
Powder X-ray diffraction patterns are acquired at ambient temperature and atmosphere on a computer-controlled Philips PW 1710 equipped with a PW3710 mpd control unit, using a monochromator, Cu Kxcex1 radiation (tube operated at 40 kV, 35 mA) and a scintillation counter. The data are collected over an angular range from 4xc2x0 to 50xc2x0 2xcex8 in continuous scan mode using a scan speed of 0.02 2xcex8/s.
The following abbreviations arc used in the examples:
Unless specified otherwise in the examples, the compounds are obtained in free (non-salt) form.